Lee, Sau KSilva, Diego GMartin, Jaime LPratama, AlvinHu, XinChang, Pheh PingWalters, GilesVinuesa, Carola2014-02-192014-02-191074-7613http://hdl.handle.net/1885/11398Overactivity of the germinal center (GC) pathway resulting from accumulation of follicular helper T (Tfh) cells causes autoimmunity, underscoring the need to understand the factors that control Tfh cell homeostasis. Here we have identifed posttranscriptional repression of interferon-y (Ifng) mRNA as a mechanism to limit Tfh cell formation. By using the sanroque lupus model, we have shown that decreased Ifng mRNA decay caused excessive IFN-g signaling in T cells and led to accumulation of Tfh cells, spontaneous GC, autoantibody formation, and nephritis. Unlike ICOS and T-bet deficiency that failed to rescue several autoimmune manifestations, interferon-y receptor (IFN-gR) deficiency prevented lupus development. IFN-y blockade reduced Tfh cells and autoantibodies, demonstrating that IFN-y overproduction was required to sustain lupus-associated pathology. Increased IFN-yR signaling caused Bcl-6 overexpression in Tfh cells and their precursors. This link between IFN-y and aberrant Tfh cell formation provides a rationale for IFN-y blockade in lupus patients with an overactive Tfh cell-associated pathway.We thank C. Gillespie for help in the preparation of electron microscopy slides, C.G.V. is supported by an Elizabeth Blackburn NHMRC fellowship. This work was funded by NHMRC program and project grants to C.G.V.13 pageshttp://www.sherpa.ac.uk/romeo/issn/1074-7613/overactivitygerminal centerautoimmunityfollicular helper T cells2012-11-1610.1016/j.immuni.2012.10.0102015-12-10